Anti-estrogens in the Clinic

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A group of drugs that have the characteristic of inhibiting the action of oestrogens are called antiestrogens. This action is achieved through the binding of these substances to estrogenic receptors by blocking them. These are found in the cells of sensitive tissues. By entering the receptor thus prevent the estrogens can occupy it thus avoiding the action of the same, another mechanism of action is through inhibition of estrogen production by enzymatic blocking of the aromatase.

-Classes according to mechanism of action:

Group 1:

They are called selective estrogen receptor modulators because they produce a different action according to the organ they occupy. That is to say, they can act as antiestrogens or as weak estrogens.
The main representative of this group is Tamoxifen and its analogues or derivatives such as Toremifen, Idoxifen, Droloxifen and Raloxifene.

Group 2:

Pure anti-oestrogens. These always inhibit oestrogenic action. (Faslodex®) is the only pure anti-oestrogen that has been clinically tested.

Group 3:

A separate group would be aromatase inhibitors, which is the enzyme that converts testosterone into estradiol: Anastrozole, Letrozole, Exemestane.
Estrogens are steroid hormones that exert multiple effects, mainly on cell proliferation and differentiation in various organs, such as hypothalamus, pituitary, uterus, breast, ovary, bone and liver. Its action in the cellular environment is exerted through a specific nuclear receptor, known as estrogen receptor (ER), which is also used by antiestrogens, thus blocking the expression of genes, action that depends on estrogenic stimulus. The human ERa gene is located on chromosome 6q and the form b gene on chromosome 14q.

-Selective ER modulators

Chemical structure and main characteristics. These compounds are non-steroidal in nature, mostly analogous to Tamoxifen. They present agonist and antagonist properties and are called Selective Estrogen Receptor Modulators (MSRE), because they can act differently depending on the target organ.
These characteristics have generated interesting expectations for their potential use in the clinic and currently some research done in this field have aimed to find the ideal MSRE, ie that the drug retains its antagonistic activity in tissues such as the breast and uterus, but maintains its estrogenic effect on bone, liver and central nervous system.
Although estrogen is commonly regarded as a female sex hormone, it also plays a critical role in men’s health. Estradiol is the main hormone responsible for bone turnover and bone quality. It is also important for cognition and regulation of certain functions of the central nervous system and metabolism.

-Excess estrogens in men and xenoestrogens:

They are chemical substances with a structure similar to estrogens that cause interferences in the natural hormonal response, blocking the hormonal receptors resulting in an excess of estrogens.
We are surrounded by them but we are not aware of them. Xenoestrogens are present in pesticides that are used to spray vegetables that we then eat. The feed that cattle are fed is also sprayed with pesticides that contain xenoestrogens that accumulate in our bodies.
Cosmetic products, such as gels, make-ups or creams that we apply on a daily basis enter through the skin, even clothing made with plastic derivatives carry these substances. Plastic food containers such as bottles, tuppers, tetrabricks, plates or plastic cutlery are also responsible for the increase in estrogen in the body.
Testosterone, through the aromatization process, is converted to estrogen, and older men have higher levels of estrogen than postmenopausal women.

Astellas Pharma has announced the publication in the New England Journal of Medicine of the results of the phase 3 pivotal clinical trial PROSPER, evaluating enzyme plus androgen deprivation therapy (ADT) versus placebo plus ADT in patients with non-metastatic castration-resistant prostate cancer (CPRC).
However, ADT reduces testosterone by up to 95% to castration levels, so they also deplete estrogen levels. Estrogen depletion can lead to serious side effects of ADT, including a high risk of bone fractures.
Perhaps one of the best-known problems in men regarding excess estrogen is gynecomastia, which is an increase in breast tissue and development of female-looking breasts.

A balance between estrogen and testosterone is important for healthy sexuality. A hormonal imbalance between estrogen and testosterone can trigger erectile dysfunction, or what is the same is the impossibility of achieving an erection.
It should be borne in mind that gynecomastia is not only an aesthetic problem in men, but is also more exposed to develop a malignant tumor.

-Main anti-oestrogens used:

However, not all act in the same way and under the same principles. Raloxifene, Danazol, Tamoxifen, Anastrozole, Clomiphene, Testolactone, Exemestane and Testolactone are some of the best known names for this type of drug.
Tamoxifen
(nolvadex 10 and 20mg.)Tamoxifen is one of the most commonly used drugs. Its purpose is to regulate estrogen receptors (MSRE). Besides giving good results eliminating male breasts, also The fertility of a man can be compromised by high levels of estrogen. Although they are responsible for the creation of sperm, an excess can produce sterility.
Clomiphene:
(omifin 50mg) is a drug composed of clomiphene citrate. It is used in women who do not ovulate and have little chance of pregnancy. During ovulation, the ovary releases an egg so that it can be fertilized by a spermatozoon, it is an MSRE, it is also used in men to improve fertility and in cases of pituitary or hypothalamic failure.
Raloxifene
(avoid 60mg.) Raloxifene belongs to a class of drugs called selective estrogen receptor modulators (SERMs). Raloxifene prevents and treats osteoporosis by mimicking the effects of estrogen (the female hormone) to increase bone density (thickness).
Danazol
(danatrol 50 100 and 200mg.)Danazol is a drug that can be prescribed to treat gynecomastia and endometriosis. It has an androgenic effect on the body which decreases the production of estrogenic hormones, acting on the FSH (follicle stimulating hormone) and LH (luteinizing hormone) of the pituitary gland.
Anastrozole
(arimidex 1 mg.) Anastrozole is a drug designed to decrease estrogen hormones and increase androgen hormones in our body. It works by blocking the enzyme aromatase.
Dosage: A 1 mg anastrozole treatment can suppress gynecomastia completely. This is mainly due to the fact that 80% of oestrogens are suppressed with this dose.
Exemestane
(aromasin 25 mg.)It is an irreversible steroid inactivator of the enzyme aromatase, structurally related to the natural substrate androstenedione. It acts as a false substrate of the enzyme aromatase, and is processed to an intermediate that irreversibly binds to the active site of the enzyme causing its inactivation.
Letrozole
(femara 2,5mg) Inhibits the enzyme aromatase by competitive binding to the aromatase cytochrome P450 heme group, resulting in a reduction of estrogen synthesis in all tissues where it is present.
Fulvestrant
(Faslodex 250mg.) The mechanism of action of the drug is based on inactivating the action of estrogens (female sex hormones) that in certain patients stimulate the growth of breast cancer. The drug is presented as a solution to administer intramuscularly, the usual dose is 500 mg once a month, is the only pure antiestrogen that has been tested in the clinic, especially in advanced breast cancer with metastasis.

It reduces the levels of expression of the progesterone receptor (RPg) and ER in breast tumors, with which there is a significant decrease in the expression of the progesterone receptor (RPg) and ER in breast tissue, without alterations in the circulating levels of LH and FSH.

Adjuvant therapy with antiestrogens has revolutionized treatment strategies for patients with malignant breast tumors that express ER, thus generating important expectations in breast cancer prevention strategies. In addition, they have begun to be used in the treatment of various diseases and symptoms associated with menopause (raloxifene for example).

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